Pharmaceutical compositions of silicon-containing substituted adenosine nucleoside amide analogs

Abstract

Novel compositions of silicon-containing anti-metabolite compounds, their preparation and use in methods for treating cancer are described. The silyl group confers lipophilicity that can enhance the penetration of the compounds across the gut wall, cell membranes and blood brain barrier, thus improving therapeutic properties including bioavailability, metabolism, and/or pharmacokinetics. The triorganosilyl group provides compounds having improved pharmacokinetics and anti-tumor activity. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for treatment of diseases and other maladies or conditions involving cancer and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.

1 . A compound of formula (I), 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is H, F, Cl, Br or NH 2 ; 
 R 2  is H, F, Cl, Br; 
 R 3  is H, O, F, Cl, Br; 
 n is an integer; 
 and wherein R 4 , R 5 , R 6  can be the same or different and can be selected from the chemical groups consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, —CH 2 CH(CH 2  CH 3 ) 2 , 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl, —CH 2 -cyclopropyl, —CH 2 -cyclohexyl, —CH 2 CH 2 -cyclopropyl, —CH 2 CH 2 -cyclohexyl, —CH 2 -indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl, p-(CH 3 ) 2 NCH 2 CH 2 CH 2 O-benzyl, p-(CH 3 ) 3 COC(O)CH 2 O-benzyl, p-(HOOCCH 2 O)-benzyl, 2-aminopyrid-6-yl, p-(N-morpholino-CH 2 CH 2 O)-benzyl, —CH 2 CH 2 C(O)NH 2 , —CH 2 -imidazol-4-yl, —CH 2 -(3-tetrahydrofuranyl), —CH 2 -thiophen-2-yl, —CH 2  (1-methyl)cyclopropyl, —CH 2 -thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, —CH 2 —C(O)O-t-butyl, —CH 2 —C(CH 3 ) 3 , —CH 2 CH(CH 2 CH 3 ) 2 , -2-methylcyclopentyl, -cyclohex-2-enyl, —CH[CH(CH 3 ) 2 ]COOCH 3 , —CH 2 CH 2 N(CH 3 ) 2 , —CH 2 C(CH 3 )═CH 2 , —CH 2 CH═CHCH 3  (cis and trans), —CH 2 OH, —CH(OH)CH 3 , —CH(O-t-butyl)CH 3 , —CH 2 OCH 3 , —(CH 2 ) 4 NH-Boc, —(CH 2 ) 4 NH 2 , —CH 2 -pyridyl (e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl), —CH 2 -naphthyl (e.g., 1-naphthyl and 2-naphthyl), —CH 2 —(N-morpholino), p-(N-morpholino-CH 2 CH 2 O)-benzyl, benzo[b]thiophen-2-yl, 5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl, 6-methoxynaphth-2-yl, —CH 2 CH 2  SCH 3 , thien-2-yl, thien-3-yl, and hydrates and solvates thereof. 
 
     
     
         2 . The compounds according to  claim 1 , selected from a group consisting of: 
       2-(8-chloro-6-((trimethylsilyl)methylamino)-9H-purin-9-yl)-5-(hydroxymethyl)-tetrahydrofuran-3,4-diol, 
       2-(8-chloro-6-((dimethyl(pentyl)silyl)methylamino)-9H-purin-9-yl)-5-(hydroxymethyl)-tetrahydrofuran-3,4-diol, 
       2-(8-chloro-6-(3-(trimethylsilyl)propylamino)-9H-purin-9-yl)-5-(hydroxymethyl)-tetrahydrofuran-3,4-diol, 
       2-(8-chloro-6-(2-methyl-4-(trimethylsilyl)phenylamino)-9H-purin-9-yl)-5-(hydroxymethyl)-tetrahydrofuran-3,4-diol, 
       2-(8-chloro-6-((dimethyl(phenyl)silyl)methylamino)-9H-purin-9-yl)-5-(hydroxymethyl)-tetrahydrofuran-3,4-diol, 
       2-(8-chloro-6-(3-(methyldiphenylsilyl)propylamino)-9H-purin-9-yl)-5-(hydroxymethyl)-tetrahydrofuran-3,4-diol, 
       2-(8-amino-6-((trimethylsilyl)methylamino)-9H-purin-9-yl)-5-(hydroxymethyl)-tetrahydrofuran-3,4-diol, 
       2-(8-amino-6-((dimethyl(pentyl)silyl)methylamino)-9H-purin-9-yl)-5-(hydroxymethyl)-tetrahydrofuran-3,4-diol, 
       2-(8-amino-6-(3-(trimethylsilyl)propylamino)-9H-purin-9-yl)-5-(hydroxymethyl)-tetrahydrofuran-3,4-diol, 
       2-(8-amino-6-(2-methyl-4-(trimethylsilyl)phenylamino)-9H-purin-9-yl)-5-(hydroxymethyl)-tetrahydrofuran-3,4-diol, 
       2-(8-amino-6-((dimethyl(phenyl)silyl)methylamino)-9H-purin-9-yl)-5-(hydroxymethyl)-tetrahydrofuran-3,4-diol, 
       2-(8-amino-6-(3-(methyldiphenylsilyl)propylamino)-9H-purin-9-yl)-5-(hydroxymethyl)-tetrahydrofuran-3,4-diol, 
       2-(2-fluoro-6-((trimethylsilyl)methylamino)-9H-purin-9-yl)-5-(hydroxymethyl)-tetrahydrofuran-3,4-diol, 
       2-(2-fluoro-6-((dimethyl(pentyl)silyl)methylamino)-9H-purin-9-yl)-5-(hydroxymethyl)-tetrahydrofuran-3,4-diol, 
       2-(2-fluoro-6-(3-(trimethylsilyl)propylamino)-9H-purin-9-yl)-5-(hydroxymethyl)-tetrahydrofuran-3,4-diol, 
       2-(2-fluoro-6-(2-methyl-4-(trimethylsilyl)phenylamino)-9H-purin-9-yl)-5-(hydroxymethyl)-tetrahydrofuran-3,4-diol, 
       2-(2-fluoro-6-((dimethyl(phenyl)silyl)methylamino)-9H-purin-9-yl)-5-(hydroxymethyl)-tetrahydrofuran-3,4-diol, 
       2-(2-fluoro-6-(3-(methyldiphenylsilyl)propylamino)-9H-purin-9-yl)-5-(hydroxymethyl)-tetrahydrofuran-3,4-diol, 
       5-(2-chloro-6-((trimethylsilyl)methylamino)-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)-tetrahydrofuran-3-ol 
       5-(2-chloro-6-((dimethyl(pentyl)silyl)methylamino)-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)-tetrahydrofuran-3-ol 
       5-(2-chloro-6-(3-(trimethylsilyl)propylamino)-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)-tetrahydrofuran-3-ol 
       5-(2-chloro-6-(2-methyl-4-(trimethylsilyl)phenylamino)-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)-tetrahydrofuran-3-ol 
       5-(2-chloro-6-((dimethyl(phenyl)silyl)methylamino)-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)-tetrahydrofuran-3-ol 
       5-(2-chloro-6-(3-(methyldiphenylsilyl)propylamino)-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)-tetrahydrofuran-3-ol 
       5-(2-chloro-6-((trimethylsilyl)methylamino)-9H-purin-9-yl)-2-(hydroxymethyl)-tetrahydrofuran-3-ol, 
       5-(2-chloro-6-((dimethyl(pentyl)silyl)methylamino)-9H-purin-9-yl)-2-(hydroxymethyl)-tetrahydrofuran-3-ol, 
       5-(2-chloro-6-(3-(trimethylsilyl)propylamino)-9H-purin-9-yl)-2-(hydroxymethyl)-tetrahydrofuran-3-ol, 
       5-(2-chloro-6-(2-methyl-4-(trimethylsilyl)phenylamino)-9H-purin-9-yl)-2-(hydroxymethyl)-tetrahydrofuran-3-ol, 
       5-(2-chloro-6-((dimethyl(phenyl)silyl)methylamino)-9H-purin-9-yl)-2-(hydroxymethyl)-tetrahydrofuran-3-ol, 
       5-(2-chloro-6-(3-(methyldiphenylsilyl)propylamino)-9H-purin-9-yl)-2-(hydroxymethyl)-tetrahydrofuran-3-ol. 
     
     
         3 . A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is H, F, Cl, Br or NH 2 ; 
 R 2  is H, F, Cl, Br; 
 R 3  is H, O, F, Cl, Br; 
 n is an integer; 
 and wherein R 4 , R 5 , R 6  can be the same or different and can include a group selected from the groups consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, —CH 2 CH(CH 2  CH 3 ) 2 , 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl, —CH 2 -cyclopropyl, —CH 2 -cyclohexyl, —CH 2 CH 2 -cyclopropyl, —CH 2 CH 2 -cyclohexyl, —CH 2 -indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl, p-(CH 3 ) 2 NCH 2 CH 2 CH 2 O-benzyl, p-(CH 3 ) 3 COC(O)CH 2 O-benzyl, p-(HOOCCH 2 O)-benzyl, 2-aminopyrid-6-yl, p-(N-morpholino-CH 2 CH 2 O)-benzyl, —CH 2 CH 2 C(O)NH 2 , —CH 2 -imidazol-4-yl, —CH 2 -(3-tetrahydrofuranyl), —CH 2 -thiophen-2-yl, —CH 2  (1-methyl)cyclopropyl, —CH 2 -thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, —CH 2 —C(O)O-t-butyl, —CH 2 —C(CH 3 ) 3 , —CH 2 CH(CH 2 CH 3 ) 2 , -2-methylcyclopentyl, -cyclohex-2-enyl, —CH[CH(CH 3 ) 2 ]COOCH 3 , —CH 2 CH 2 N(CH 3 ) 2 , —CH 2 C(CH 3 )═CH 2 , —CH 2 CH═CHCH 3  (cis and trans), —CH 2 OH, —CH(OH)CH 3 , —CH(O-t-butyl)CH 3 , —CH 2 OCH 3 , —(CH 2 ) 4 NH-Boc, —(CH 2 ) 4 NH 2 , —CH 2 -pyridyl (e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl), —CH 2 -naphthyl (e.g., 1-naphthyl and 2-naphthyl), —CH 2 —(N-morpholino), p-(N-morpholino-CH 2 CH 2 O)-benzyl, benzo[b]thiophen-2-yl, 5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl, 6-methoxynaphth-2-yl, —CH 2 CH 2  SCH 3 , thien-2-yl, thien-3-yl, and hydrates and solvates thereof; and an inert carrier. 
 
     
     
         4 . A method for treatment of a subject having a condition or disorder comprising administering to the subject a therapeutically effective amount of A compound of formula (I), 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is H, F, Cl, Br or NH 2 ; 
 R 2  is H, F, Cl, Br; 
 R 3  is H, O, F, Cl, Br; 
 n is an integer; 
 and wherein R 4 , R 5 , R 6  can be the same or different and can be selected from the chemical groups consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, —CH 2 CH(CH 2  CH 3 ) 2 , 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl, —CH 2 -cyclopropyl, —CH 2 -cyclohexyl, —CH 2 CH 2 -cyclopropyl, —CH 2 CH 2 -cyclohexyl, —CH 2 -indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl, p-(CH 3 ) 2 NCH 2 CH 2 CH 2 O-benzyl, p-(CH 3 ) 3 COC(O)CH 2 O-benzyl, p-(HOOCCH 2 O)-benzyl, 2-aminopyrid-6-yl, p-(N-morpholino-CH 2 CH 2 O)-benzyl, —CH 2 CH 2 C(O)NH 2 , —CH 2 -imidazol-4-yl, —CH 2 -(3-tetrahydrofuranyl), —CH 2 -thiophen-2-yl, —CH 2  (1-methyl)cyclopropyl, —CH 2 -thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, —CH 2 —C(O)O-t-butyl, —CH 2 —C(CH 3 ) 3 , —CH 2 CH(CH 2 CH 3 ) 2 , -2-methylcyclopentyl, -cyclohex-2-enyl, —CH[CH(CH 3 ) 2 ]COOCH 3 , —CH 2 CH 2 N(CH 3 ) 2 , —CH 2 C(CH 3 )═CH 2 , —CH 2 CH═CHCH 3  (cis and trans), —CH 2 OH, —CH(OH)CH 3 , —CH(O-t-butyl)CH 3 , —CH 2 OCH 3 , —(CH 2 ) 4 NH-Boc, —(CH 2 ) 4 NH 2 , —CH 2 -pyridyl (e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl), —CH 2 -naphthyl (e.g., 1-naphthyl and 2-naphthyl), —CH 2 —(N-morpholino), p-(N-morpholino-CH 2 CH 2 O)-benzyl, benzo[b]thiophen-2-yl, 5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl, 6-methoxynaphth-2-yl, —CH 2 CH 2  SCH 3 , thien-2-yl, thien-3-yl, and hydrates and solvates thereof. 
 
     
     
         5 . The method of  claim 4 , in which the condition or disorder is angiogenesis. 
     
     
         6 . The method of  claim 4 , in which the condition or disorder is cancer. 
     
     
         7 . The method of  claim 4 , in which the condition or disorder is a hematologic malignancy. 
     
     
         8 . The method of  claim 4 , in which the condition or disorder is the hematologic malignancy known as multiple myeloma. 
     
     
         9 . The method of  claim 4 , in which the condition or disorder is the a hematologic malignancy chronic known as lymphocytic leukemia. 
     
     
         10 . The method of  claim 4 , in which the condition or disorder is a hematologic malignancy and R 1  is an amino or chloride group. 
     
     
         11 . The method of  claim 4 , wherein the subject is a mammal. 
     
     
         12 . The method of  claim 4 , wherein the subject is human. 
     
     
         13 . A method for treating a neoplasia in a subject in need of such treatment wherein the method comprises treating the subject with an amount of radiation and a radiation-potentiating amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof wherein: the amount of radiation and the amount of the compound of  claim 1  together comprise a neoplasia-treating-effective amount, and the neoplasia is sensitive to such treatment. 
     
     
         14 . The compound of claim ( 1 ) wherein the compound is a diasteriomer, racemate, or single enantioner. 
     
     
         15 . The pharmaceutical composition of  claim 3  further comprising a second active agent. 
     
     
         16 . The pharmaceutical composition of  claim 3  further comprising a second active agent comprising an antineoplastic agent or growth inhibiting agent. 
     
     
         17 . The pharmaceutical composition of  claim 15  wherein the antineoplastic agent is an antimetabolite-type antineoplastic agent. 
     
     
         18 . The pharmaceutical composition of  claim 15  wherein the antineoplastic agent is an alkylating-type antineoplastic agent. 
     
     
         19 . The pharmaceutical composition of  claim 15  wherein the antineoplastic agent is an antibiotic-type antineoplastic agent. 
     
     
         20 . The pharmaceutical composition of  claim 15  wherein the antineoplastic agent is of antineoplastic agents selected from the group consisting of alpha-carotene, alpha-difluoromethyl-arginine, acitretin, Biotec AD-5, Kyorin AHC-52, alstonine, amonafide, amphethinile, amsacrine, Angiostat, ankinomycin, anti-neoplaston A10, antineoplaston A2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, Henkel APD, aphidicolin glycinate, asparaginase, Avarol, baccharin, batracylin, benfluoron, benzotript, Ipsen-Beaufour BIM-23015, bisantrene, Bristo-Myers BMY-40481 Vestar boron-10, bromofosfamide, Wellcome BW-502, Wellcome BW-773, caracemide, carmethizole hydrochloride, Ajinomoto CDAF, chlorsulfaquinoxalone, Chemes CHX-2053, Chemex CHX-100, Warner-Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941, Warner-Lambert CI-958, clanfenur, claviridenone, ICN compound 1259, ICN compound 4711, Contracan, Yakult Honsha CPT-11, crisnatol, curaderm, cytochalasin B, cytarabine, cytocytin, Merz D-609, DABIS maleate, dacarbazine, datelliptinium, didemnin-B, dihaematoporphyrin ether, dihydrolenperone, dinaline, distamycin, Toyo Pharmar DM-341, Toyo Pharmar DM-75, Daiichi Seiyaku DN-9693, elliprabin, elliptinium acetate, Tsumura EPMTC, ergotamine, etoposide, etretinate, fenretinide, Fujisawa FR-57704, gallium nitrate, genkwadaphnin, Chugai GLA-43, Glaxo GR-63178, grifolan NMF-5N, hexadecylphosphocholine, Green Cross HO-221, homoharringtonine, hydroxyurea, BTG ICRF-187, ilmofosine, isoglutamine, isotretinoin, Otsuka JI-36, Ramot K-477, Otsuak K-76COONa, Kureha Chemical K-AM, MECT Corp KI-8110, American Cyanamid L-623, leukoregulin, lonidamine, Lundbeck LU-23-112, Lilly LY-186641, NCI (US) MAP, marycin, Merrel Dow MDL-27048, Medco MEDR-340, merbarone, merocyanine derivatives, methylanilinoacridine, Molecular Genetics MGI-136, minactivin, mitonafide, mitoquidone, mopidamol, motretinide, Zenyaku Kogyo MST-16, N-(retinoyl)amino acids, Nisshin Flour Milling N-021, N-acylated-dehydroalanines, nafazatrom, Taisho NCU-190, nocodazole derivative, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782, NCI NSC-95580, octreotide, Ono ONO-112, oquizanocine, Akzo Org-10172, pancratistatin, pazelliptine, Warner-Lambert PD-111707, Warner-Lambert PD-115934, Warner-Lambert PD-131141, Pierre Fabre PE-1001, ICRT peptide D, piroxantrone, polyhaematoporphyrin, polypreic acid, Efamol porphyrin, probimane, procarbazine, proglumide, Invitron protease nexin I, Tobishi RA-700, razoxane, Sapporo Breweries RBS, restrictin-P, retelliptine, retinoic acid, Rhone-Poulenc RP-49532, Rhone-Poulenc RP-56976, SmithKline SK&F-104864, Sumitomo SM-108, Kuraray SMANCS, SeaPharm SP-10094, spatol, spirocyclopropane derivatives, spirogermanium, Unimed, SS Pharmaceutical SS-554, strypoldinone, Stypoldione, Suntory SUN 0237, Suntory SUN 2071, superoxide dismutase, Toyama T-506, Toyama T-680, taxol, Teijin TEI-0303, teniposide, thaliblastine, Eastman Kodak TJB-29, tocotrienol, Topostin, Teijin TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028, ukrain, Eastman Kodak USB-006, vinblastine sulfate, vincristine, vindesine, vinestramide, vinorelbine, vintriptol, vinzolidine, with anolides or Yamanouchi YM-534. 
     
     
         21 . The pharmaceutical composition of  claim 15  wherein the second active agent is a radioprotective protective agent. 
     
     
         22 . The composition of  claim 1  or  claim 3  wherein n is 1-6.